Toward Improving the Selectivity of Organic Halide Electrocarboxylation with Mechanistically Informed Solvent Selection

The use of a liquid electrolyte is nearly ubiquitous in electrosynthetic systems and can have a significant impact on the selectivity and efficiency of electrochemical reactions. Solvent selection is thus a key step during optimization, yet this selection process usually involves trial-and-error. As a step toward more rational solvent selection, this work examines how the electrolyte solvent impacts the selectivity of electrocarboxylation of organic halides. For the carboxylation of a model alkyl bromide, hydrogenolysis is the primary side reaction. Isotope-labeling studies indicate the hydrogen atom in the hydrogenolysis product comes solely from the aprotic electrolyte solvent. Further mechanistic studies reveal that under synthetically relevant electrocarboxylation conditions, the hydrogenolysis product is formed via deprotonation of the solvent. Guided by these mechanistic findings, a simple computational descriptor based on the free energy to deprotonate a solvent molecule was shown to correlate strongly with carboxylation selectivity, overcoming limitations of traditional solvent descriptors such as pKa. Through careful mechanistic analysis surrounding the role of the solvent, this work furthers the development of selective electrocarboxylation systems and more broadly highlights the benefits of such analysis to electrosynthetic reactions.


■ INTRODUCTION
Synthetic electro-organic chemistry has experienced a surge in popularity due to its chemoselectivity stemming from precise potential control and mild conditions coupled with renewable energy compatibility. 1−6 Electro-organic systems generally use liquid electrolytes comprising an ionic salt dissolved in a molecular solvent. By mole number, solvent molecules are the major species in most electrolytes for electro-organic synthesis, so the reactive and solvating properties of the solvent can have a profound influence on the rates and selectivities of electrochemical reactions. Choosing an appropriate solvent for an electrochemical reaction is crucial and can be facilitated by having appropriate solvent selection guidelines that reduce the amount of trial-and-error experimentation needed.
All liquid-phase reaction development requires careful solvent selection to ensure compatibility with reactants, products, and additives. At the outset, typical considerations include the coordinating ability, proticity, and possibly pK a of the solvent. For electro-organic reactions, an additional consideration is the electrochemical stability window of the solvent, typically measured with an inert supporting electrolyte. 7,8 These initial considerations can narrow the scope of solvents to test, but the exact role of the solvent in a reaction may not be obvious at the outset. As with conventional synthesis, numerous electrosynthetic studies have observed important product selectivity changes induced by the electro-lyte solvent choice, 1,9−12 many of which have been ascribed to various nonreactive roles including selectively changing oxidation potentials, 13 acting as a mediator, 14 modifying nucleophilicity, 15 and coordinating ionic intermediates. 16 A number of studies have shown that solvent molecules can also be reactive in electrochemical systems, which can be desirable for achieving certain types of products. 17,18 For electrochemical systems, the application of a voltage can enable the creation of intermediates that are much more reactive than starting materials or products, complicating the solvent selection process. Thus, obtaining mechanistic understanding of how the solvent impacts reaction outcomes is an important task to enable proper solvent choice.
An important class of electro-organic reactions is reductive cross-coupling of organic halides with electrophiles. These transformations can generate new carbon−carbon 19,20 or carbon−heteroatom 21 bonds�both desirable transformations in industrial and synthetic organic chemistry. Protic solvents have been found to accelerate the reduction of many types of carbon−halogen bonds on catalytic electrodes 22,23 and can even alter the reaction mechanism relative to that in an aprotic solvent. 24 In these cases, protic solvents accelerate the hydrogenolysis of the carbon−halogen bond, which is usually undesirable for organic synthesis, although site-specific deuteration with D 2 O is one promising application. 25 Among aprotic solvents, cleavage rates of carbon−halogen bonds have been correlated to the Lewis acidity of the solvent, which impacts its ability to solubilize the halogen anion byproduct. 26−29 While these studies examined how the solvent impacts the rates and mechanism of electrochemical carbon− halogen bond cleavage, understanding of how the solvent affects the product selectivity of electrochemical cross-coupling reactions involving organic halides is lacking.
To probe the role of the solvent on the selectivity of carbon−carbon bond formation, the electrochemical carboxylation of organic halides with carbon dioxide (CO 2 ) is used as a model reaction (Scheme 1). This reaction scheme is promising because it can use sustainable energy (renewable electricity) and an abundant, renewable C 1 carbon source (CO 2 ) to construct a wide variety of valuable carboxylic acids. 30−32 The use of applied potential can also eliminate the need for highly reactive organometallic reagents 5 and can enable precise control over kinetic driving forces, leading to improved functional group tolerance. 33 Although electrocarboxylation can be inherently more selective than traditional organometallic reagents, it can be plagued by the undesirable electrochemical hydrogenolysis of the carbon−halogen bond. Prior work has suggested that the selectivity of electrocarboxylation over hydrogenolysis can depend rather strongly on the choice of aprotic solvent, 33 motivating an in-depth mechanistic study into the role(s) of the solvent. In this work, the aprotic solvent is shown to provide the hydrogen atoms for the hydrogenolysis side product during electrocarboxylation. The mechanism of the hydrogenolysis side reaction is elucidated with respect to the aprotic solvent, revealing that deprotonation of the solvent is the dominant pathway toward the hydrogenolysis product under synthetically relevant conditions for making carboxylic acids. These results are used to construct a computational molecular descriptor for solvents that correlates strongly with carboxylation selectivity and outperforms standard solvent descriptors from the literature such as pK a .

■ RESULTS AND DISCUSSION
Origin of the Hydrogenolysis Product. A number of possible sources of hydrogen atoms and protons exist in typical electrocarboxylation electrolytes, including the solvent molecules, electrolyte ions such as tetra-n-butylammonium (TBA), trace amounts of water, and even the substrate itself. Trace water can be particularly reactive because protic solvents are known to accelerate reductive cleavage of carbon−halogen bonds for many types of organic halides. 22,23 To identify the source of hydrogen atoms in the hydrogenolysis product, carboxylation reactions were conducted in both deuterated dimethyl sulfoxide (DMSO-d 6 ) and deuterated acetonitrile (MeCN-d 3 ), and the fraction of hydrogenolysis product containing deuterium was quantified. Both solvents were distilled and dried over 3 Å molecular sieves to reduce the chances of impurities, especially water, in the solvents influencing the results (see the Supporting Information). As a model organic halide, 1-bromo-3-phenylpropane (1a) was used because the rates of carboxylation and hydrogenolysis are comparable under electrochemical conditions. 33 Electrochemical experiments were conducted in a single-compartment cell with a sacrificial aluminum anode and a silver cathode. Bromide ions were found to be necessary to enable oxidation of the aluminum anode, so a mixture of TBA-BF 4 and TBA-Br was used (see the Supporting Information).
The hydrogenolysis of 1a produces the hydrocarbon product n-propylbenzene (1b). In a deuterated solvent with otherwise protic compounds, either a hydrogen or deuterium atom can replace the bromine in 1a. A combination of nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) was used to confirm the replacement of the carbon−bromine bond with a carbon−deuterium bond. The mass spectrum of 1b after carboxylation in DMSO-d 6 shows the primary mass peak increases by one relative to that of a commercial standard of 1b, consistent with the incorporation of a single deuterium nucleus into the product ( Figure 1A). The increased mass only persists for the first set of peaks, indicating that the deuterium is on the terminal carbon of the propyl chain. The presence of deuterium on the terminal carbon is also confirmed by 2 H NMR which shows a deuterium peak in the aliphatic region ( Figure 1B). Additional triplet splitting on the terminal carbon protons by deuterium can also be observed by 1 H NMR ( Figure S4). These spectroscopic results collectively prove a significant amount of 1b contains a deuterium at the terminal carbon after carboxylation in a deuterated solvent.
To probe the origin of the hydrogen atom in 1b more thoroughly, electrocarboxylation experiments were performed (1) in two different anhydrous, deuterated solvents (DMSO-d 6 and MeCN-d 3 ), (2) at both low and high conversion of 1a, and (3) at constant current and constant potential. The deuterated fraction was quantified either from the ratio of the m/z 121 and 120 peaks from MS or from the ratio of the integrated proton signals at the terminal and internal carbon atoms ( Figure 1C). Under all conditions, the vast majority of the hydrogenolysis product contains deuterium (Table 1). On the basis of these results, solvent hydrogen atoms are the primary source of the hydrogenolysis product under synthetically relevant electrocarboxylation conditions.
Hydrogenolysis Mechanism under Electrocarboxylation Conditions. In the case of carboxylation and other crosscoupling reactions involving organic halides, hydrogenolysis products are not desirable. However, studying the hydro-

Scheme 1. Competition between Carboxylation and Hydrogenolysis for the Model Alkyl Halide 1-Bromo-3phenylpropane (1a)
genolysis mechanism can provide insights into which properties of the solvent control the predominance of this pathway. For the electrochemical reduction of carbon−halogen bonds, the first step is widely accepted to involve a concerted or stepwise cleavage of the carbon−halogen bond, forming a halide anion and a carbon radical (Scheme 2). 34−37 The use of catalytic electrodes such as silver 38 and substrates without lowlying π* orbitals 37 favors the concerted pathway, as is the case in this work. Once the carbon−halogen bond is cleaved, hydrogenation of the organic radical intermediate can proceed via either radical hydrogen abstraction (1e − process) or anionic deprotonation (2e − process). 39 Carboxylation may also proceed from either the radical or anionic intermediate in a 2e − process. To facilitate rational solvent selection, the predominant hydrogenolysis pathway needs to be identified because each pathway involves a different reactive property of the solvent.
Linear sweep voltammetry indicates the presence of two electrochemical reactions during the reduction of 1a on silver in DMF (Figure 2A). The first peak likely corresponds to the reductive cleavage of the carbon−bromine bond to discharge a bromide anion and form an adsorbed organic species or an organoradical. The presence of an organic radical intermediate was confirmed by the formation of a coupling product when the radical trap 4-vinylanisole was added ( Figures S20−S23).
The second cathodic peak has a much greater peak current than that of the first. It displays a dependence on the concentration of 1a, and the peak current is proportional to the square root of the scan rate ( Figure S7). These observations are consistent with the second peak arising from transport limitations. The reduction of organic (R • (ads) ) or solvent radical species (Solv • (ads) ) could be responsible for the current at the second reduction peak: The presence of possibly adsorbed solvent species could arise from hydrogen atom abstraction by the organic species. Both species would only be generated after the initial one-electron reduction of 1a, so the reduction of both would also become limited by mass transport of 1a. Distinguishing between these two processes is key to understanding the hydrogenolysis mechanism.   To clarify which reaction is occurring at the second cathodic peak, the reduction of 1a was conducted in the presence of deuterated ethanol (EtOD). This deuterated additive was selected because the −OD group should be susceptible to deprotonation but not to deuterium abstraction. 39 To avoid the formation of adsorbed deuterium, which could react with radical intermediates, potentials were kept more positive of −2.6. V vs Me 10 Fc 0/+ (all potentials in this work are referenced to decamethylferrocene), which is the observed onset potential for EtOD reduction on silver in DMF ( Figure S5). The presence of EtOD does induce higher hydrogenolysis rates at potentials where direct EtOD reduction does not occur. Notably, the radical trap 4-vinylanisole does not induce similar increases in the hydrogenolysis rate ( Figure S22), indicating that EtOD is not accelerating hydrogenolysis via a radical pathway. This observation is also in line with a previous work which found that protic solvents accelerate the electrochemical reduction of organic halides. 22 Because the hydrogenolysis rate increases in its presence, EtOD does not react with already formed carbanion intermediates and suggests a possible concerted proton−electron transfer (CPET). Notwithstanding this limitation, EtOD can be used to obtain important mechanistic insights about the hydrogenolysis mechanism via changes in the deuteration of products as discussed below.
Examining the incorporation of deuterium into the hydrogenolysis product 1b and the solvent enables identification of the process occurring at the second cathodic peak. The fraction of deuterated alkane shows a statistically significant drop (p < 9.1 × 10 −6 ) going from −2.0 to −2.1 V, while remaining fairly constant on either side of this drop ( Figure 2B). The origin of the decrease in the deuterated fraction of 1b is a more rapid increase in the formation rate of protonated 1b compared to that for deuterated 1b beginning around −2.1 V (Figure 2C). At the same time, a statistically significant increase in the amount of deuterium is seen only at the formyl position (p < 7.1 × 10 −3 ) in DMF beginning at −2.1 V ( Figure 2D). This observation indicates that the formyl position is deprotonated below −2.1 V. This result is in agreement with DFT calculations which predict the formyl proton is the most acidic in DMF (Table S8).
On the basis of these observations, the mechanism that is most consistent with the above data for the electrochemical process at the second cathodic peak is the reduction of R • (ads) to 1b by deprotonation of the solvent at voltages more cathodic than −2.1 V. If this process corresponded to reduction of a solvent radical, the deuterated fraction would have remained unchanged, which is not observed. Moreover, the reduction of R • (ads) to 1b would clear the surface of adsorbed species, resulting in higher current densities, consistent with observed product formation rates. Similar trends are observed when varying the initial concentration of 1a and switching the solvent to MeCN (Figures S17 and S19), indicating this mechanism is not unique to DMF. Additional experiments confirm that the observed changes in deuterium incorporation are not a result of solvent−EtOD exchange reactions but are genuinely due to the applied potential ( Figure  S19). These mechanistic insights about the hydrogenolysis pathway can be leveraged to understand electrocarboxylation selectivities. The ratio of the amount of carboxylic acid (1c) to the amount of hydrogenolysis product (1b) is used as a metric for carboxylation selectivity and is denoted as the carbox-   Table S4. ylation-to-hydrogenolysis ratio (CHR). The CHR displays a strong dependence on the applied potential ( Figure 3A). Similar to the results with EtOD, a sharp decrease in the CHR by about a factor of 4 occurs beginning around −2.0 V. The carboxylation rate also increases significantly after −2.1 V, although the hydrogenolysis rate increases by a proportionally larger amount, leading to lower CHRs ( Figure 3B). Although the CHR is relatively high at potentials more anodic of −2.1 V, the rate of carboxylation is too low for synthetic purposes. Only at potentials more cathodic of −2.1 V can carboxylation occur at synthetically relevant rates on silver. As shown earlier by the deuterium incorporation experiments, the mechanism of hydrogenolysis at potentials more cathodic of −2.1 V involves deprotonation of the solvent. Taken together, solvent deprotonation is the primary hydrogenolysis pathway under synthetically relevant electrocarboxylation conditions. Solvent-Based Descriptor for Carboxylation Selectivity. The previous discussion showed that under practical carboxylation conditions in DMF the majority of the hydrogenolysis product originates from deprotonation of DMF rather than from hydrogen abstraction. On the basis of similarities between LSVs of 1a in other solvents to its LSV in DMF ( Figure S25), a reasonable assumption is that the hydrogenolysis product primarily originates from solvent deprotonation across a wide range of solvents under practical electrocarboxylation conditions. This assumption can be leveraged to develop a solvent-based descriptor that correlates strongly with carboxylation selectivity. Such a descriptor would harness mechanistic understanding to facilitate the discovery and design of improved solvents for electrochemical carboxylation of organic halides and potentially other electrochemical reductive cross-coupling reactions.
To ensure the robustness of any observed correlations, carboxylation was performed in a variety of solvents ( Figure  4A) under several conditions, including both constant current (−5 mA/cm 2 ) and constant potential electrolyses. For constant potential electrolyses, three different potentials were selected. Two potentials were based on the peak potential of the second cathodic peak from LSVs in each solvent (0 and −160 mV), and the third was a constant potential relative to Me 10 Fc 0/+ (−2.3 V). Using potentials relative to the second cathodic peak potential ensures similar operating regimes (i.e., whether solvent deprotonation or hydrogen abstraction is predominant) across solvents, while holding potential constant relative to Me 10 Fc 0/+ keeps the chemical potential of electrons in the cathode consistent across solvents.
For all experimental conditions, the CHR was used as the experimental data against which to assess the descriptors. Although mass transport does affect the reduction of 1a under most of the conditions tested, the CHR is a selectivity metric and should not depend too strongly on the amount of 1a near the electrode surface. We have examined transport limitations of CO 2 in our system and found they should not influence the results ( Figure S29). Carboxylation and hydrogenolysis products comprised the vast majority of products derived from the reduction of 1a in all tested solvents (Tables S4−S7), which further supports only needing to examine the CHR to assess carboxylation selectivity.
Because hydrogenolysis primarily occurs via solvent deprotonation, a natural choice for a solvent-based descriptor would be the pK a of the solvent. While solvent pK a does display a moderate correlation with CHR ( Figure S12), directly measuring the pK a of many aprotic solvent molecules relevant for electrocarboxylation is not feasible due to their high basicities (e.g., DMF). Other commonly used solvent parameters such as Kamlet−Taft parameters and Gutmann numbers either fail to have a strong correlation with CHR or are not sensitive enough to differentiate solvents with the highest CHRs ( Figure S12). Because of the limitations of experimental descriptors available in the literature, a computational descriptor based on the free energy of deprotonating a solvent molecule (ΔG an , formation energy of a solvent anion) was employed. The protonation of a carbanion (R − ) can be used as a reference reaction, although this specific choice does not qualitatively influence the results.
The advantage of this type of descriptor is that it can be rapidly calculated for any arbitrary solvent molecule and avoids calculating energies of solvated protons, enabling efficient screening of a wide variety of candidate solvents.
To compute ΔG an , density functional theory (DFT) calculations with continuum solvation (PCM) at the M06-2X/def2-TZVPD level of theory were used. 40−44 Less expensive DFT methods could also be used to calculate descriptors that correlated to experimental CHRs nearly as well as those from M06-2X/def2-TZVPD + PCM ( Figure S13). Because many of these solvents have more than one deprotonation site, only the most acidic (i.e., most negative ΔG an ) site was used to for the descriptor. As a check, we generated a composite descriptor incorporating the deprotonation energies of all the C−H bonds in each solvent (Q an , see the Supporting Information). These computational descriptors were evaluated to determine how well they correlated to the experimentally observed CHRs from the selected solvents.
For a variety of different polar, aprotic solvents ( Figure 4A), a strong correlation is observed between the calculated ΔG an and the experimentally observed CHR under both constant current and constant potential experiments (Figures S10 and 4B). As the solvent molecule becomes harder to deprotonate (less negative ΔG an ), the CHR generally increases, in agreement with the expected trend if solvent deprotonation is controlling the amount of hydrogenolysis product created. In particular, the best correlation (r = 0.92) is observed for the experiments conducted at −160 mV of the second cathodic peak ( Figure 4B). Out of the conditions tested, this potential is the most cathodic, which helps reduce the importance of hydrogen abstraction, leaving carboxylation and solvent deprotonation as the primary pathways for the reduction of 1a. The composite descriptor Q an performed similarly to ΔG an since all of the solvents examined have one C−H bond that is much more easily deprotonated than the rest ( Figure S11). The lowest free energy of abstracting a hydrogen, ΔG rad , and its composite descriptor, Q rad , show no correlation with CHR, consistent with solvent deprotonation being the primary hydrogenolysis pathway at potentials relevant to practical carboxylation ( Figure S11).
The easiest solvent to deprotonate within the selection, Nmethylformamide (NMF), displayed almost negligible carboxylation activity, with hydrogenolysis predominating. Solvents more acidic than NMF would also be expected to be fairly poor for carboxylation. At the other end, the two solvents most resistant to deprotonation, DMF and 1,3-dimethyl-2-imidazolidinone (DMI), showed the highest CHRs. The remaining solvents are clustered together; these solvents share the similar characteristic of having a-CH 2 or -CH 3 alpha to an unsaturated Journal of the American Chemical Society pubs.acs.org/JACS Article electron-withdrawing group (carbonyl or nitrile). These α-CH x protons are known to be acidic and represent an undesirable functional group to have in a solvent for selective electrocarboxylation.
To further support the use of the DFT-derived ΔG an , these computational values were compared to an experimental acidity metric developed in this work. This metric is based off of the exchange rate between EtO − and the solvent, as measured by deuterium incorporation into the solvent during electrolysis with EtOD using 2 H NMR. The log−linear relationship between ΔG an and the amount of deuterium exchange confirms that ΔG an is representative of how easily C−H bonds in aprotic solvents are deprotonated ( Figure S28).
Benzylic halides are also common substrates in carboxylation and cross-coupling reactions. To gain a sense of how important the solvent may be for other types of organic halides, (1bromoethyl)benzene (2a) was carboxylated in the same series of solvents (Scheme 3). 2a reduces more easily than 1a as a result of benzylic stabilization of intermediate radicals and anions ( Figure S26). The CHR values after carboxylation of 2a are above 20 in all solvents except NMF. Furthermore, no correlation could be found between the anionic or radical DFT descriptors ( Figure S15). The carboxylation selectivity of 2a is already high, so beyond NMF, solvent acidity properties no longer have a significant impact. Carboxylation of 2a in MeCN-d 3 resulted in only partial deuteration of the hydrogenolysis product, which suggests that trace water or other impurities may become relevant at these low hydrogenolysis rates. In context, CHRs for alkyl halides are fairly sensitive to solvent choice while for benzylic halides, CHRs are rather independent of the solvent beyond a certain acidity limit.

■ CONCLUSIONS
The choice of solvent is a critical design parameter for electrosynthetic reactions, yet this selection is often done empirically from a limited set of solvents. In the case of electrocarboxylation of organic halides with CO 2 at heterogeneous cathodes, the solvent can play a decisive role in the selectivity of the reaction by controlling the rate of the competing hydrogenolysis side reaction. Through mechanistic investigations, this work showed that hydrogenolysis products incorporate hydrogen atoms derived from the aprotic solvent and that under synthetically relevant conditions, hydrogenolysis occurs via solvent deprotonation rather than hydrogen abstraction. On the basis of this mechanistic understanding, a computational solvent descriptor involving the free energy to deprotonate a solvent molecule was formulated. This descriptor is readily calculable by standard DFT methods for any arbitrary solvent molecule and was found to give a strong correlation with carboxylation selectivity. A deuterium exchange rate experiment confirmed the appropriateness of the DFT descriptor to capture the ease of solvent deprotonation. Common empirical solvent descriptors were unable to correlate with experimental carboxylation selectivities as strongly as the DFT descriptor across all tested solvents. The sensitivity of carboxylation selectivity to the solvent is a function of substrate choice, with benzylic halides having carboxylation selectivities that are almost independent of the solvent choice while alkyl halides depend more strongly on the solvent choice. These results not only provide a tool to select better performing solvents for carboxylation but also illustrate how a mechanistic understanding can facilitate rational solvent selection in electrochemical reactions. ■ ASSOCIATED CONTENT
Detailed experimental procedures, additional product distribution data, product characterization, descriptor correlations, electrochemical characterization, and DFT optimized geometries (PDF) Engineering Discovery Environment (XSEDE) Expanse cluster at the SDSC through allocation CHE200049, which is supported by National Science Foundation Grant ACI-1548562.